Programming of a developmental imbalance in hypothalamic glutamatergic/GABAergic afferents mediates low basal activity of the hypothalamic-pituitary-adrenal axis induced by prenatal dexamethasone exposure in male offspring rats
Programming of a developmental imbalance in hypothalamic glutamatergic/GABAergic afferents mediates low basal activity of the hypothalamic-pituitary-adrenal axis induced by prenatal dexamethasone exposure in male offspring rats
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下丘脑谷氨酸/GABA能传入神经发育失衡的编程介导产前地塞米松暴露引起的雄性子代大鼠下丘脑-垂体-肾上腺轴基础活性低下
DOI：
10.1016/j.toxlet.2020.05.022
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发表时间：
2020-10-01
影响因子：
3.5
通讯作者：
Wang, Hui
中科院分区：
文献类型：
--
作者：
Lu, Juan;Li, Qiang;Wang, Hui
本研究旨在证明孕期地塞米松暴露(PDE)可导致雄性子代大鼠下丘脑-垂体-肾上腺轴(HPAA)基础活动降低，并探讨其机制。妊娠第9天至第20天，皮下注射地塞米松0.2 mg/kg/d。雄性GD20胎鼠及出生后第1天取成年雄性子代大鼠85只，麻醉下处死。取GD20胎鼠下丘脑细胞，用不同浓度的地塞米松和糖皮质激素受体(GR)拮抗剂米非司酮处理5d。结果提示，地塞米松通过激活GR，进一步刺激谷氨酸向γ-氨基丁酸的转化，使下丘脑室旁核(PVN)的谷氨酸/GABA能传入神经元失衡，从而增强下丘脑GAD-67的表达。这种失衡的改变在出生后保持不变，导致小细胞神经元受到抑制，并介导了PDE子代大鼠HPAA基础活性的降低，表现为血液中促肾上腺皮质激素和皮质酮水平下降，以及下丘脑促肾上腺皮质激素释放激素(CRH)和精氨酸加压素(AVP)表达水平下降。PVN内谷氨酸/GABA能传入神经元的发育失衡是导致雄性PDE大鼠HPAA基础活性降低的潜在机制之一。
This study was intended to demonstrate that prenatal dexamethasone exposure (PDE) can induce low basal activity of the hypothalamic-pituitary-adrenal axis (HPAA) in male offspring rats and explore the underlying mechanism. Pregnant rats were subcutaneously administered 0.2 mg/kg/d dexamethasone from gestational day (GD) 9 to GD20. Male GD20 fetuses and postnatal day 85 adult male offspring rats were sacrificed under anesthesia. Hypothalamic cells were from GD20 similar to postnatal day (PD) 7 fetal male rats, treated with different concentrations of dexamethasone and the glucocorticoid receptor (GR) antagonist mifepristone for 5 days. The results suggested that dexamethasone enhanced the expression of hypothalamic L-glutamic acid decarboxylase (GAD) 67 by activating GR, further stimulating the conversion of glutamate to gamma-aminobutyric acid (GABA) and inducing an imbalance in glutamatergic/GABAergic afferents in the hypothalamic paraventricular nucleus (PVN). This imbalance change was maintained postnatally, leading to the inhibition of parvocellular neurons, and mediating the low basal activity of the HPAA in PDE offspring rats, which was manifested by decreased levels of blood adrenocorticotropic hormone and corticosterone as well as reduced expression levels of corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) in the hypothalamus. Programming of a developmental imbalance in glutamatergic/GABAergic afferents in the PVN is a potential mechanism responsible for low basal activity of the HPAA in male PDE rats.